Abstract 271: NF-kB Mediated Modulation of mir-23b/-130a-axis is Critical for Cardiac Remodeling

Abstract

Cardiac remodeling is a process that alters structural and functional determinants of myocardium in response to hemodynamic stress resulted in left ventricular hypertrophy, fibrosis leading to heart failure. Pressure overload that induces cardiac remodeling involves both cardiomyocytes (CM) and cardiac fibroblasts (CF) cross-talk for the development of adverse remodeling. The miRNAs are a new class of post-transcriptional regulator capable of repressing gene expression by base pairing to the 3' UTR of mRNA targets; involved in diverse cardiac diseases. However, the function of miRNAs in cellular cross-talk leading to cardiac remodeling remains elusive. Previously, we showed that inhibition of NF-kB prevents cardiac remodeling; however, NF-κB mediated miRNAs’ role in cardiac remodeling remains elusive. We will test the hypothesis that NF-κB dependent miR-23b/-130a is a pathogenic niche regulating the cardiac remodeling; and inhibition of miR-23b/-130a abrogates the adverse remodeling by restoring PPARg-PTEN-axis. We have identified a panel of novel dysregulated miRNAs in the left ventricle of wild type mice subjected to thoracic aortic constriction (TAC). The dysregulated miRNAs were restored in cardiac-specific IκBα triple-mutant transgenic mice (3M) subjected to TAC indicated NF-kB dependent regulation. We observed that miR-130a and miR-23b were significantly upregulated in TAC and Ang II infusion and were inhibited in 3M-TAC mice. We identified PPARg-PTEN-axis, a bona-fide target for miR-23b/-130a after unbiased in vitro screening. Inhibition of NF-kB normalized miR-23b/-130a expression and the target genes in Ang II and TGFb1 stimulated CM and CF. Inhibition of miR-130a showed reduction of cell sizes in CM and decrease cellular proliferation in CF indicated a cellular cross-talk. The in vivo inhibition of miR-130a in wild-type mice after Ang II infusion significantly reduced cardiac remodeling, restoring PPARg-PTEN level and improved cardiac function. Our findings provide evidence that miR-23b/-130a displays a critical role in the pathogenesis of cardiac remodeling. We conclude that miR-23b/-130a could be a triggering factor in cardiac remodeling and providing new mechanistic information for therapeutic benefit.